Brain-Derived Extracellular Vesicles Induce Vasoconstriction and Reduce Cerebral Blood Flow in Mice.
Brain-Derived Extracellular Vesicles Induce Vasoconstriction and Reduce Cerebral Blood Flow in Mice.
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DOI：
10.1089/neu.2021.0274
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发表时间：
2022-03
影响因子：
4.2
通讯作者：
Ji-wei Wang;Xiaofeng Xie;Yingang Wu;Yuan Zhou;Qi-feng Li;Ying Li;Xin Xu;Min Wang;Lydia S. Murdiyarso;Katie L. Houck;Tristan Hilton;Dominic Chung;Min Li;Jian-Ning Zhang;Jingfei Dong
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作者：
Ji-wei Wang;Xiaofeng Xie;Yingang Wu;Yuan Zhou;Qi-feng Li;Ying Li;Xin Xu;Min Wang;Lydia S. Murdiyarso;Katie L. Houck;Tristan Hilton;Dominic Chung;Min Li;Jian-Ning Zhang;Jingfei Dong
外伤性脑损伤（TBI）损害脑血管自身调节，减少脑血流量（CBF），导致缺血性继发性损伤。我们已经证明，受伤的大脑释放脑源性细胞外囊泡（BDEVs）进入循环，在循环中，它们引起全身高凝状态，并迅速转变为消耗性凝血病。BDEVs诱导内皮损伤和通透性，导致假设它们有助于tbi诱导的脑血管失调。在一项旨在验证这一假设的研究中，我们检测了严重TBI后C57BL/6J小鼠的循环BDEVs，在损伤后3小时达到3x104/µl的峰值水平（占总膜联蛋白v结合ev的71.2±21.5%）。我们进一步在适应性转移模型中发现，注入3x104/µl BDEVs后，41.7±5.8%的未损伤小鼠在6小时内死亡。BDEVs通过血管壁迁移，通过诱导血管平滑肌细胞钙内流诱导血管快速收缩，在输注后30分钟内使CBF降低93.8±5.6%。CBF抑制在最终死亡的小鼠中持续存在，但在存活的小鼠中很快恢复。它是由钙通道阻滞剂尼莫地平预防的。当从致死数量的BDEVs中分离出蛋白质或磷脂成分时，它们都不会引起血管收缩、CBF减少和死亡。这些结果表明，BDEVs具有一种新的血管收缩活性，这种活性依赖于BDEVs的结构，并与tbi诱导的播散性脑缺血和猝死有关。
Traumatic brain injury (TBI) impairs cerebrovascular autoregulation and reduces cerebral blood flow (CBF), leading to ischemic secondary injuries. We have shown that injured brains release brain-derived extracellular vesicles (BDEVs) into circulation, where they cause a systemic hypercoagulable state that rapidly turns into consumptive coagulopathy. BDEVs induce endothelial injury and permeability, leading to the hypothesis that they contribute to TBI-induced cerebrovascular dysregulation. In a study designed to test this hypothesis, we detected circulating BDEVs in C57BL/6J mice subjected to severe TBI, reaching peak levels of 3x104/µl at 3 hours post injury (71.2±21.5% of total annexin V-binding EVs). We further showed in an adaptive transfer model that 41.7±5.8% of non-injured mice died within 6 hours after being infused with 3x104/µl of BDEVs. BDEVs transmigrated through the vessel walls, induced rapid vasoconstriction by inducing calcium influx in vascular smooth muscle cells, and reduced CBF by 93.8±5.6% within 30 minutes after infusion. The CBF suppression was persistent in mice that eventually died but it recovered quickly in surviving mice. It was prevented by the calcium channel blocker nimodipine. When being separated, neither protein nor phospholipid components from the lethal number of BDEVs induced vasoconstriction, reduced CBF, and caused death. These results demonstrate a novel vasoconstrictive activity of BDEVs that depends on the structure of BDEVs and contributes to TBI-induced disseminated cerebral ischemia and sudden death.